2. Academic Validation
  3. Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

  • Bioorg Med Chem. 2015 May 1;23(9):2010-23. doi: 10.1016/j.bmc.2015.03.017.
Daigo Hayashi 1,  Naoki Tsukioka 1,  Yutaka Inoue 1,  Yoshiki Matsubayashi 1,  Toshimasa Iizuka 1,  Kazuhiro Higuchi 2,  Yoji Ikegami 1,  Tomomi Kawasaki 3
Affiliations

Affiliations

  • 1 Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
  • 2 Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address: khiguchi@my-pharm.ac.jp.
  • 3 Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address: kawasaki@my-pharm.ac.jp.
PMID: 25835358 DOI: 10.1016/j.bmc.2015.03.017
Abstract

An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b-q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast Cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure-activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.

Keywords

ABCG2 modulator; Ardeemin; Multicomponent reaction; Multidrug resistance; Suzuki–Miyaura coupling.

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